Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and is associated with high morbidity and mortality. Increased activation of Signal Transducer and Activator of Transcription-3 (STAT3) has been implicated in OSCC tumorigenesis and progression. The mechanisms of STAT3 hyperactivation in OSCC are incompletely understood. Preliminary data suggests that the receptor-like protein tyrosine phosphatase T (PTPRT) directly dephosphorylates, and thus inactivates, STAT3 in OSCC preclinical models. Recent reports from our group and The Cancer Genome Atlas (TCGA) have demonstrated promoter methylation or mutation of PTPRT in a relatively high proportion of OSCC tumors (60% and 5.5%, respectively of 347 tumors analyzed to date). Further investigation showed that expression of OSCC-derived PTPRT mutants leads to increased STAT3 activation in OSCC cells. We therefore hypothesize that loss-of-function (LOF) of PTPRT by mutation or promoter methylation contributes to STAT3-mediated growth and survival pathways in OSCC. We therefore predict that OSCC tumors harboring LOF alterations of PTPRT will exhibit increased sensitivity to STAT3 pathway inhibition, ultimately allowing the identification of a subgroup of patients who are most likely to respond to STAT3 pathway inhibitors. We will investigate the above hypotheses via the following specific aims: Specific Aim 1: To determine the effect of OSCC tumor-derived PTPRT mutations on phosphatase activity and the contribution of PTPRT mutations to growth, survival, and sensitivity to STAT3 pathway inhibition in OSCC preclinical models. Specific Aim 2: To investigate PTPRT promoter methylation in OSCC human tumors and cell lines and determine the contribution of PTPRT loss to OSCC tumorigenesis, progression, and sensitivity to STAT3 pathway inhibition in vivo using a PTPRT KO mouse model.